Inhibitory Effects of Antivascular Endothelial Growth Factor Strategies in Experimental Dopamine-Resistant Prolactinomas

Abstract

Prolactin-secreting adenomas are the most frequent type among pituitary tumors, and pharmacological therapy with dopamine agonists remains the mainstay of treatment. But some adenomas are resistant, and a decrease in the number or function of dopamine D2 receptors (D2Rs) has been described in these cases. D2R knockout [Drd2(Ϫ/Ϫ)] mice have chronic hyperprolactinemia and pituitary hyperplasia and provide an experimental model for dopamine agonist-resistant prolactinomas. We described previously that disruption of D2Rs increases vascular endothelial growth factor (VEGF) expression. We therefore designed two strategies of antiangiogenesis using prolactinomas generated in Drd2(Ϫ/Ϫ) female mice: direct intra-adenoma mVEGF R1 (Flt-1)/Fc chimera (VEGF-TRAP) injection for 3 weeks [into subcutaneously transplanted pituitaries from Drd2(Ϫ/Ϫ) mice] and systemic VEGF neutralization with the specific monoclonal antibody G6-31. Both strategies resulted in substantial decrease of prolactin content and lactotrope area, and a reduction in tumor size was observed in in situ prolactinomas. There were significant decreases in vascularity, evaluated by cluster of differentiation molecule 31 vessel staining, and proliferation (proliferating cell nuclear antigen staining) in response to both anti-VEGF treatments. These data demonstrate that the antiangiogenic approach was effective in inhibiting the growth of in situ dopamine-resistant prolactinomas as well as in the transplanted adenomas. No differences in VEGF protein expression were observed after either anti-VEGF treatment, and, although serum VEGF was increased in G6-31-treated mice, pituitary activation of the VEGF receptor 2 signaling pathway was reduced. Our results indicate that, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate vascular supply and represent a supplementary therapeutic target in dopamine agonist-resistant prolactinomas.

Hypoxia-induced VEGF production ‘RSUMEs’ in pituitary adenomas

“…In support of the recent report by Luque et al (2011) that demonstrated inhibitory effects of anti-VEGF strategies in experimental dopamine-resistant prolactinomas, these findings suggest an important role of VEGF signaling in pituitary tumor growth. Pituitary tumors may have a lower microvessel density compared with the highly vascularized normal pituitary gland, but hypoxic conditions within the tumor may still activate the RSUME-HIF1a-VEGF pathway leading to increased vascularization or more ordered microvascular geometry in order to sustain tumor growth.…”

New targeted therapies in pituitary carcinoma resistant to temozolomide

“…Indeed, it has been demonstrated that VEGF expression was associated with pituitary tumorigenesis [14] and somatostatin analogues (octreotide or pasireotide) inhibit NFPA cell viability by inhibiting VEGF secretion [15]. Moreover, recent studies demonstrated that the antiangiogenic approach using anti-VEGF antibody [16] or a small-molecule tyrosine kinase inhibitor (lapatinib) [17] targeting EGF receptors Erb1 and Erb2 was effective, in inhibiting in vivo the growth of dopamineresistant prolactinoma from dopamine receptor D2R mouse knockout [16] or in estrogen-induced Fischer344 rat prolactinomas [17]. More recently, Liu et al identified a pharmacologic CDK2/cycline E inhibitor, R-roscovitine, and demonstrated that R-roscovitine suppressed ACTH expression and induced ACTH tumor cell senescence using a transgenic fish model and AtT20 ACTH tumor cells injected in nude mice [18].…”

Transformujący czynnik wzrostu β1 (TGFβ1) i naczyniowo-śródbłonkowy czynnik wzrostu (VEGF) we krwi ludzi zdrowych i chorych z orbitopatią Gravesa — nowy mechanizm działania glikokortykosteroidów?

“…Disease processes which have been shown to increase vascularity include, in particular, endocrine glands illness [24,25], acromegaly [19], pituitary adenomas [26,27], autoimmune thyroid disease, goitre, neoplasms [18,22] and eye disorders -retinopathy occurring in premature infants [18,28], diabetic retinopathy [18,20,21,[29][30][31], uveitis and other ocular illnesses. Angiogenesis commonly occurs in inflammatory diseases [18-20, 22, 24-27].…”

“…Angiogenesis is an important component of many physiological and pathological processes [16][17][18][19][20][21][22][23][24][25][26][27]. Disease processes which have been shown to increase vascularity include, in particular, endocrine glands illness [24,25], acromegaly [19], pituitary adenomas [26,27], autoimmune thyroid disease, goitre, neoplasms [18,22] and eye disorders -retinopathy occurring in premature infants [18,28], diabetic retinopathy [18,20,21,[29][30][31], uveitis and other ocular illnesses.…”